Dowell Alexander C, Munford Haydn, Goel Anshita, Gordon Naheema S, James Nicholas D, Cheng K K, Zeegers Maurice P, Ward Douglas G, Bryan Richard T
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom.
Bladder Cancer Research Centre, Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom.
Front Oncol. 2021 Feb 25;11:626748. doi: 10.3389/fonc.2021.626748. eCollection 2021.
The use of immune checkpoint blockade, in particular PD-1 and PD-L1 inhibitors, is now commonplace in many clinical settings including the treatment of muscle-invasive bladder cancer (MIBC). Notwithstanding, little information exists regarding the expression of the alternative PD-1 ligand, PD-L2 in urothelial bladder cancer (UBC). We therefore set out to characterise the expression of PD-L2 in comparison to PD-L1. Firstly, we assessed PD-L2 expression by immunohistochemistry and found widespread expression of PD-L2 in UBC, albeit with reduced expression in MIBC. We further investigated these findings using RNA-seq data from a cohort of 575 patients demonstrating that PDCD1LG2 (PD-L2) is widely expressed in UBC and correlated with CD274 (PD-L1). However, in contrast to our immunohistochemistry findings, expression was significantly increased in advanced disease. We have also provided detailed evidence of constitutive PD-L2 expression in normal urothelium and propose a mechanism by which PD-L2 is cleaved from the cell surface in MIBC. These data provide a comprehensive assessment of PD-L2 in UBC, showing PD-L2 is abundant in UBC and, importantly, constitutively present in normal urothelium. These data have implications for future development of immune checkpoint blockade, and also the understanding of the function of the immune system in the normal urinary bladder.
免疫检查点阻断疗法，尤其是PD - 1和PD - L1抑制剂，如今在包括肌肉浸润性膀胱癌（MIBC）治疗在内的许多临床环境中已普遍应用。尽管如此，关于尿路上皮膀胱癌（UBC）中另一种PD - 1配体PD - L2的表达情况，目前所知甚少。因此，我们着手对PD - L2与PD - L1的表达特征进行比较。首先，我们通过免疫组织化学评估了PD - L2的表达，发现其在UBC中广泛表达，尽管在MIBC中表达有所降低。我们利用来自575名患者队列的RNA测序数据进一步研究了这些发现，结果表明程序性死亡配体1LG2（PD - L2）在UBC中广泛表达且与CD274（PD - L1）相关。然而，与我们免疫组织化学的结果相反，在晚期疾病中其表达显著增加。我们还提供了正常尿路上皮中组成型PD - L2表达的详细证据，并提出了一种在MIBC中PD - L2从细胞表面被切割的机制。这些数据对UBC中的PD - L2进行了全面评估，表明PD - L2在UBC中含量丰富，重要的是，在正常尿路上皮中持续存在。这些数据对免疫检查点阻断疗法的未来发展以及对正常膀胱中免疫系统功能的理解都具有重要意义。
